After menopause, hypertension and cardiovascular risk increases in women. Our preliminary data indicate that a comparable susceptibility to hypertension can be observed following slow pressor angiotensin II (AngII) infusion in a menopausal mouse model. The hypothalamic paraventricular nucleus (PVN) is critical for integrating and coordinating neurohumoral responses involved in cardiovascular regulation. In hypertension, NMDA receptor activation and NADPH oxidase-dependent reactive oxygen species (ROS) production in PVN neurons that project to the spinal cord plays a pivotal role in enhancing the sympathetic drive that underlies the elevation of arterial pressure. A significant number of PVN-spinal neurons contain the estrogen receptor (ER) , suggesting that hormone alterations in menopause could selectively influence excitation in this population. In particular, gonadal steroids could alter excitatory transmission by regulating the expression and/or subcellular distribution of the NMDA receptor, voltage-gated Ca2+ channel currents and/or the generation of NADPH oxidase derived ROS. Such changes could ultimately contribute to the development of hypertension observed in menopause. Therefore, this proposal will test the central hypothesis that changes in postsynaptic NMDA receptors and associated signaling pathways within ER PVN neurons during menopause predisposes these neurons to increase excitability in response to hypertensive challenges. Two aims will examine mouse models of menopause to determine (1) whether menopause increases the susceptibility to slow pressor AngII hypertension through mechanisms involving post-synaptic NMDA receptors in the PVN; and (2) if NMDA-mediated responses in ER-containing PVN neurons show adaptations consistent with the potentiation of excitatory transmission during the development of hypertension. These studies will be conducted in the well-established intact aging model and the new VCD model of menopause including some ER-GFP transgenic mice, and will use slow pressor AngII- infusion as the hypertensive challenge. These studies will be achieved using a multidisciplinary approach including high resolution electron microscopic immunolabeling to identify the subcellular distribution of essential NMDA NR1 receptors and related signaling pathway components in ER-GFP labeled PVN neurons, spatial-temporal deletion of the NR1 gene, quantitative RT-PCR, patch-clamp recording, ROS imaging, and telemetric measurement of blood pressure. PUBLIC HEALTH RELEVANCE: Young women are less susceptible to developing hypertension than their male counterparts. However, during menopause women develop an increased incidence of hypertension and related cerebrovascular complications that can surpass that of men. The proposed studies will provide novel information about the neurobiology of a cardiovascular hypothalamic circuit that is particularly sensitive to fluctuations in hormone levels that may significantly contribute to increased susceptibility to hypertension. Moreover, they may provide the mechanistic basis for developing more effective therapeutic strategies for the management of post-menopausal increases in blood pressure.